J Vet Intern Med 2015;29:1098–1104
Pulse-Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs J.H. Burton, R.O. Venable, D.M. Vail, L.E. Williams, C.A. Clifford, S.M. Axiak-Bechtel, A.C. Avery, and D.H. Thamm Background: Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy. Hypothesis/Objectives: The primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine. Animals: Forty-seven client-owned dogs with measurable MCT. Methods: Toceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m2. All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone. Results: The MTD of lomustine was established at 50 mg/m2 when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy. Conclusions and clinical importance: Combined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT. Key words: Cancer; Chemotherapy; Dog; Tyrosine kinase inhibitor.
From the Flint Animal Cancer Center, Department of Clinical Sciences, Colorado State University, Fort Collins, CO (Burton, Venable and Thamm); the School of Veterinary Medicine and the Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI (Vail); the Department of Clinical Sciences, North Carolina State University, Raleigh, NC (Williams); the Red Bank Veterinary Hospital, Tinton Falls, NJ (Clifford); the Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO (Axiak-Bechtel); and the Flint Animal Cancer Center, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO (Avery); Dr. Burton’s present address is Department of Surgical and Radiological Sciences, University of California, Davis, Davis, CA; Dr. Venable’s present address is Arizona Veterinary Oncology, Gilbert, AZ; Dr. William’s present address is Veterinary Specialty Hospital of the Carolinas, Cary, NC; Dr. Clifford’s present address is Hope Veterinary Specialists, Malvern, PA. This was presented in abstract form at the Veterinary Cancer Society meeting, October, 2012, Las Vegas, NV and October, 2013, Minneapolis, MN. Patients were enrolled at the Flint Animal Cancer Center, Colorado State University Veterinary Medical Center (CSU-VMC), School of Veterinary Medicine, University of Wisconsin-Madison (UW-SVM), Veterinary Medical Teaching Hospital, University of Missouri (MU-VMTH), Red Bank Veterinary Hospital and the Veterinary Health Complex, North Carolina State University (NCSU-VHC). Corresponding author: Dr D.H. Thamm, Flint Animal Cancer Center, Department of Clinical Sciences, Colorado State University, 300 W. Drake Road, Fort Collins, CO 80523-1620; e-mail: doug.
[email protected].
Submitted January 30, 2015; Revised April 1, 2015; Accepted May 14, 2015. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. DOI: 10.1111/jvim.13573
Abbreviations: ALT alanine transaminase ALP alkaline phosphatase CR complete response DLT dose-limiting toxicity ITD internal tandem duplication MCT mast cell tumor MTD maximally tolerated dose ORR objective response rate OS overall survival PR partial response PFS progression-free survival PD progressive disease RECIST response evaluation criteria in solid tumors SD stable disease TOC toceranib phosphate TTMR time to maximal response TKI tyrosine kinase inhibitor VCOG-CTCAEVeterinary Co-operative Oncology Group – Common Terminology Criteria for Adverse Events
ast cell tumors (MCT) are the most common cutaneous tumors in the dog and are generally successfully treated with wide surgical excision alone.1–3 Therapeutic challenges, however, arise with MCT that are large or infiltrative, high grade, have metastasized beyond the regional lymph node, or are located where wide surgical excision is not possible. Several medical treatments have been studied for MCT in dogs, including corticosteroids alone, lomustine, chlorambucil, hydroxyurea, and vinblastine as well as various combinations of these agents.4–11 Although generally well tolerated, response rates frequently
M
Pulse Toceranib Plus Lomustine
remain at or below 50% and usually are brief and incomplete.4–12 The tyrosine kinase inhibitor (TKI), toceranib phosphate (TOC), has demonstrated single-agent antitumor activity against MCT in dogs, but fewer than half of the dogs with MCT experience objective tumor regression with only 14% experiencing complete responses (CR).13 The TKI sunitinib and radiation therapy are synergistic in preclinical models of pancreatic adenocarcinoma, soft tissue sarcoma, and breast cancer in humans14–16 as well as between TOC and radiation therapy in dogs with MCT.17 In addition, several studies have identified potentiation of the efficacy of paclitaxel, doxorubicin, and vincristine by the TKI imatinib in human preclinical models of KIT-positive melanoma and Ewing’s sarcoma,18–20 presumably owing to downregulation of important antiapoptotic pathways. A recent phase I study evaluating the safety of the combination vinblastine and TOC in dogs reported the necessity for substantial dose reductions of vinblastine in this combination therapy to prevent frequent and severe neutropenia.21 Together, these data suggest that combination therapies with TKIs may improve efficacy over single-agent treatments alone. Clinically relevant adverse effects can be observed with continuous long-term TKI administration, including diarrhea, inappetence, neutropenia, proteinuria, fatigue, and musculoskeletal pain, resulting in the need for drug holidays and dose reductions.13,22,23 Pulse administration of TKIs with chemotherapy potentially may chemosensitize tumor cells while decreasing cost and toxicity associated with chronic TKI administration. This phase I/II multicenter clinical trial sought to determine the maximally tolerated dose (MTD), tolerability and adverse event profile of combined treatment with pulse-administered TOC, and lomustine in dogs with measurable MCT. The second objective of this study was to determine the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in dogs with measurable MCT treated with combined pulse-administered TOC and lomustine, and to identify potential prognostic factors in dogs treated with this combination. We hypothesized that the combination of pulse-administered TOC and lomustine would be well tolerated and efficacious when administered to dogs with cutaneous MCT.
Materials and Methods Patient Selection Client-owned dogs with histologically or cytologically confirmed MCT ≥10 mm in longest diameter, where surgical excision was not feasible or was declined by the owner, were considered for enrolment. Eligibility criteria included Veterinary Co-operative Oncology Group – Common Terminology Criteria for Adverse Events (VCOG-CTCAE) constitutional health score of 0 (normal activity) or 1 (mildly decreased from baseline)24, and life expectancy of >6 weeks. Dogs were required to have adequate hematologic, renal, and hepatic function to safely undergo treatment; defined as ≥2,500 neutrophils/lL, ≥75,000 platelets/lL, PCV ≥28%, serum creatinine concentration ≤29 the upper limit of normal (ULN),
1099
total serum bilirubin concentration
